The overall objective of this grant is an in-depth investigation of esophageal function in health and disease as it relates to gastroesophago- pharyngeal reflux and aspiration. Gastroesophageal reflux disease is the most common malady of the esophagus. It is estimated that 7-10% of the US population suffers from various degrees of this disease. This translates into a significant burden on health care resources. However, complications of reflux disease induced outside the esophagus; namely in the aerodigestive and airway tracts, are now becoming increasingly recognized. For example, it is estimated that 4- 10% of laryngeal diseases seen in ENT clinics are associated with reflux disease. Our specific objectives are: A) To determine the patho- physiological basis of supraesophageal complications of gastroesophageal reflux disease. This section will include: characterization and quantification of gastroesophago-pharyngeal reflux with special emphasis on the association between reflux-induced esophageal and supraesophageal lesions; 2) characterization of the defensive mechanisms against aspiration of gastroesophago-pharyngeal reflux, including a) characterization of the mechanisms of esophagopharyngeal reflux of gastric acid in controls and patients with reflux laryngitis, and b) defining the airway protective mechanisms against pharyngolaryngeal reflux of gastric content in controls and GERD patients. The hypothesis that patients with reflux-induced laryngeal lesions have abnormalities of one or more of the airway protective mechanisms against reflux of gastric content will be tested. These include abnormalities of lower esophageal sphincter function, esophageal body motor response to distension, esophagoglottal closure reflex, UES resting tone and esophago-UES contractile reflex, pharyngo-UES contractile reflex and activation of pharyngeal-induced swallows, and pharyngoglottal closure reflex. B) Neural mechanisms of esophageal sensory motor function in relation to gastroesophago-pharyngeal reflux will be investigated. We will l) determine, in a feline model, the brainstem and reflex control of airway protective mechanisms, 2) identify the cerebral cortical regions involved in esophageal viscero sensation, and 3) characterize the effect of inhibitory influence of pharyngeal stimulation on esophageal peristalsis and bolus transport, LES tone and gastroesophageal reflux in normal controls and GERD patients and we will expand our mathematical modeling effort to include the airway protective reflexes during gastroesophageal reflux. Individual, but interrelated protocols are proposed to achieve our objectives and will be executed by our multidisciplinary, interdepartmental team.